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Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents¹

Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305

A widely held tenet of present day oncology is that tumor cells treated with anticancer agents die from apoptosis, and that cells resistant to apoptosis are resistant to cancer treatment. We suggest, in this review, that this tenet may need to be reexamined for human tumors of nonhematological origin, for two principal reasons: (a) cell killing has often been assessed in short term assays that are more influenced by the rate, than the overall level, of cell killing. This has tended to underestimate cell killing for cells not susceptible to apoptosis or having mutant p53; and (b) conclusions from experiments with normal cells transformed with dominant oncogenes have often been extrapolated to tumor cells. This does not take into account the fact that tumor cells have invariably undergone selection to an apoptotically resistant phenotype. In this review, we examine the impact of these two factors with particular emphasis on the influence of mutations in p53 on the sensitivity of tumor cells to DNA-damaging agents. We find that because wild-type p53 predisposes cells to a more rapid rate of cell death after DNA damage, particularly with normal or minimally transformed cells, that short-term assays have led to the conclusion that mutations in p53 confer resistance to genotoxic agents. On the other hand, if clonogenic survival is used to assess killing in cells derived from actual solid human tumors, then apoptosis and the genes controlling it, such as p53 and bcl-2, appear to play little or no role in the sensitivity of these cells to killing by anticancer drugs and radiation.

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				K. L. MURPHY, A. P. DENNIS, and J. M. ROSEN A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model FASEB J, November 1, 2000; 14(14): 2291 - 2302. [Abstract] [Full Text]

				I. Petak, D. M. Tillman, and J. A. Houghton p53 Dependence of Fas Induction and Acute Apoptosis in Response to 5-Fluorouracil-Leucovorin in Human Colon Carcinoma Cell Lines Clin. Cancer Res., November 1, 2000; 6(11): 4432 - 4441. [Abstract] [Full Text] [PDF]

				F. M. Yakes, B. D. Wamil, F. Sun, H.-P. Yan, C. E. Carter, and C. G. Hellerqvist CM101 Treatment Overrides Tumor-induced Immunoprivilege Leading to Apoptosis Cancer Res., October 1, 2000; 60(20): 5740 - 5746. [Abstract] [Full Text]

				R. J. Sleiman and B. W. Stewart Early Caspase Activation in Leukemic Cells Subject to Etoposide-induced G2-M Arrest: Evidence of Commitment to Apoptosis Rather Than Mitotic Cell Death Clin. Cancer Res., September 1, 2000; 6(9): 3756 - 3765. [Abstract] [Full Text]

				S. Hietanen, S. Lain, E. Krausz, C. Blattner, and D. P. Lane Activation of p53 in cervical carcinoma cells by small molecules PNAS, July 18, 2000; 97(15): 8501 - 8506. [Abstract] [Full Text] [PDF]

				M. S. Orr, P. M. O'Connor, and K. W. Kohn Effects of c-erbB2 Overexpression on the Drug Sensitivities of Normal Human Mammary Epithelial Cells J Natl Cancer Inst, June 21, 2000; 92(12): 987 - 994. [Abstract] [Full Text] [PDF]

				M. L. Smith, J. M. Ford, M. C. Hollander, R. A. Bortnick, S. A. Amundson, Y. R. Seo, C.-X. Deng, P. C. Hanawalt, and A. J. Fornace Jr. p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/or gadd45 Genes Mol. Cell. Biol., May 15, 2000; 20(10): 3705 - 3714. [Abstract] [Full Text]

				Y. Nieto, P. J. Cagnoni, S. Nawaz, E. J. Shpall, R. Yerushalmi, B. Cook, P. Russell, J. McDermit, J. Murphy, S. I. Bearman, et al. Evaluation of the Predictive Value of Her-2/neu Overexpression and p53 Mutations in High-Risk Primary Breast Cancer Patients Treated With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation J. Clin. Oncol., May 10, 2000; 18(10): 2070 - 2080. [Abstract] [Full Text] [PDF]

				K. Hofland, B. O. Petersen, J. Falck, K. Helin, P. B. Jensen, and M. Sehested Differential Cytotoxic Pathways of Topoisomerase I and II Anticancer Agents after Overexpression of the E2F-1/DP-1 Transcription Factor Complex Clin. Cancer Res., April 1, 2000; 6(4): 1488 - 1497. [Abstract] [Full Text]

				O. Potapova, M. Gorospe, R. H. Dougherty, N. M. Dean, W. A. Gaarde, and N. J. Holbrook Inhibition of c-Jun N-Terminal Kinase 2 Expression Suppresses Growth and Induces Apoptosis of Human Tumor Cells in a p53-Dependent Manner Mol. Cell. Biol., March 1, 2000; 20(5): 1713 - 1722. [Abstract] [Full Text]

				S. W. Lowe and A. W. Lin Apoptosis in cancer Carcinogenesis, March 1, 2000; 21(3): 485 - 495. [Abstract] [Full Text] [PDF]

				T. Otsuki, O. Yamada, J. Kurebayashi, T. Moriya, H. Sakaguchi, H. Kunisue, K. Yata, M. Uno, Y. Yawata, and A. Ueki Estrogen Receptors in Human Myeloma Cells Cancer Res., March 1, 2000; 60(5): 1434 - 1441. [Abstract] [Full Text]

				T. A. H. Jarvinen, M. Tanner, V. Rantanen, M. Barlund, A. Borg, S. Grenman, and J. Isola Amplification and Deletion of Topoisomerase II{alpha} Associate with ErbB-2 Amplification and Affect Sensitivity to Topoisomerase II Inhibitor Doxorubicin in Breast Cancer Am. J. Pathol., March 1, 2000; 156(3): 839 - 847. [Abstract] [Full Text] [PDF]

				M. Wade and M. J. Allday Epstein-Barr Virus Suppresses a G2/M Checkpoint Activated by Genotoxins Mol. Cell. Biol., February 15, 2000; 20(4): 1344 - 1360. [Abstract] [Full Text]

				Z. Zhang, Q. Liu, L. E. Lantry, Y. Wang, G. J. Kelloff, M. W. Anderson, R. W. Wiseman, R. A. Lubet, and M. You A Germ-Line p53 Mutation Accelerates Pulmonary Tumorigenesis: p53-independent Efficacy of Chemopreventive Agents Green Tea or Dexamethasone/myo-Inositol and Chemotherapeutic Agents Taxol or Adriamycin Cancer Res., February 1, 2000; 60(4): 901 - 907. [Abstract] [Full Text]

				K. Newton and A. Strasser Ionizing Radiation and Chemotherapeutic Drugs Induce Apoptosis in Lymphocytes in the Absence of Fas or FADD/MORT1 Signaling: Implications for Cancer Therapy J. Exp. Med., January 3, 2000; 191(1): 195 - 200. [Abstract] [Full Text] [PDF]